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Complementary and Alternative Medicine Series

Soy and Women's Health

Tori Hudson, ND

Soybeans have been a staple of Asian diets for centuries. They found their way into the American diet, by way of France and England, in the 1700s but have only gained a measure of popularity fairly recently. Soybeans are prized for their high protein content-approximately 38%. Of the remaining content, 18% is fat (primarily polyunsaturated fats, with only a small amount of saturated fats); 15% is insoluble carbohydrates; 14% is a combination of moisture, ash, and miscellaneous compounds; and 13% is soluble carbohydrates. Soy also contains many common vitamins and minerals, including calcium, iron, zinc, copper, magnesium, niacin, pyridoxine, and folic acid.

Perhaps the most well known components of soy are isoflavones, a type of phytoestrogen. These isoflavones behave like weak estrogens, and can bind to estrogen receptors in the uterus, breast, brain, bone, and arteries. Of interest, although they weakly mimic estrogen's effects in some tissues, they can block estrogen's effects in other tissues. Part of the controversy about soy revolves around this ability to selectively modulate estrogen receptors. Soy also generates a small amount of concern because of its occasional poor digestibility, potential mineral-blocking effects, and potential interference with thyroid function.

Soy, especially in the form of cooked soybeans, is difficult for some people to digest. Trypsin inhibitors contained in soybeans can block enzymes needed for protein digestion, resulting in fermentation and gas production. As few trypsin inhibitors remain in the beans after processing, however, most people do not have this problem with soy. Phytates in soybeans can block the uptake of minerals such as calcium, magnesium, iron, and zinc. Although the phytate content of soybeans is higher than that of other legumes or grains, the mineral-blocking effect of phytates is reduced when soybeans are eaten with meat or fish. Phytates are also reduced in fermented soy products such as tempeh and miso. If soy foods are consumed as part of a healthful, varied diet, adequate minerals should be retained.

Genistein and daidzein can also inhibit thyroid hormone synthesis.¹ In fact, excessive soy isoflavone consumption (approximately 200 mg/d or greater) has been implicated in diet-induced goiter. This problem is not likely to occur in persons who consume an average amount of soy in their diets and in those who maintain a healthful, varied diet.

SOY ISOFLAVONES
Soybeans, which contain 1 to 2 mg of isoflavones per gram of soy protein, are the richest food source of isoflavones. Not all soy-protein products contain isoflavones, however. Some soy powders and capsules are processed with an alcohol extract that removes the isoflavones. In order to ensure that soy users will be receiving the desired daily dose of isoflavones, they should ascertain the isoflavone content of the particular soy food or product chosen.

Types
Soybeans contain three different isoflavones: genistein, daidzein, and glycitein. Genistein has a six-fold greater affinity for the b estrogen receptor than the a estrogen receptor, which explains why its action depends on the nature of the estrogen receptors in each particular tissue. For example, it may act as a proestrogen in bone, but an antiestrogen in the breast.

Mechanisms of Action
Genistein, with 1/400 to 1/1000 the potency of estradiol, appears to have a weak estrogenic effect.^2,3 At higher concentrations and in different tissues, however, it can selectively exert an antiestrogenic effect. In some tissues, it may weakly bind to estrogen receptors, thereby inhibiting endogenous or exogenous estrogen from binding to those receptors. Herein lies an important, but poorly understood, property of genistein and other isoflavones: their selectivity in terms of where they act as proestrogens and where they act as antiestrogens. Genistein's selectivity also depends on dose: In the absence of physiologic estrogen, low-dose genistein has weak estrogenic effects and can stimulate cell growth, including estrogen-receptor-positive breast cancer cells in a test tube.^4,5 In contrast, a higher dose inhibits breast cancer cell growth.^4,5

Because of their aromatase-inhibiting effects, isoflavones can block conversion of androstenedione to estrogen, thereby reducing serum estradiol levels. Thus, less estrogen is available to bind to estrogen receptors. Isoflavones also seem to stimulate sex hormone-binding globulin (SHBG) synthesis in the liver,⁶ thereby reducing the relative amounts of free estradiol and free testosterone and the biologic activity of these sex hormones. (Vegetarians are known to have high SHBG levels, which may be related to their phytoestrogen-rich diets.^7-9) This mechanism of action may yet be another avenue for reducing estrogen's effect on tissues such as the breast.

Genistein also inhibits tyrosine kinases, which appear to play a role in cell proliferation and transformation. Circulating levels of tyrosine kinase-inhibiting substances may have anticancer effects.^10,11 In addition, genistein has an antiangiogenic effect,¹² which may have implications for the treatment of hereditary hemorrhagic telangiectasias and cancerous tumors that are dependent on a blood supply.

Several studies have shown that both daidzein and genistein inhibit free radicals,¹³ and that genistein increases the activity of antioxidant enzymes such as glutathione peroxidase, glutathione reductase, and superoxide dismutase.¹¹ Isoflavones can also protect against the oxidation of low-density lipoprotein (LDL) cholesterol, which may aid in preventing atherosclerosis.

CLINICAL EFFECTS
Soy isoflavones have various beneficial effects (and perhaps, a few potentially harmful effects) on women's health.

Hot Flashes
Brzezinski et al placed 145 women with menopausal symptoms on a phytoestrogen-rich diet (25% of their daily caloric intake was composed of soybean foods and flaxseeds) or a control diet for 12 weeks.¹⁴ The soy/flaxseed group, as compared with the controls, experienced greater overall symptomatic improvement, although the difference between groups was not significant. However, when symptoms were evaluated separately, reductions in hot flashes and vaginal dryness were significantly greater in the soy/flaxseed group than in the controls.

Albertazzi et al investigated the effects of dietary soy supplementation on hot flashes in 104 postmenopausal women.¹⁵ Fifty-one subjects received 60 g of isolated soy protein daily (76 mg of isoflavones) and 53 received 60 g of casein (placebo) daily for 12 weeks. By the end of the study, the number of hot flashes decreased by 45% in the soy group versus 30% in the placebo group, a significant difference. Similarly, Eden et al found that a diet including 160 mg of isoflavones daily for 3 months significantly reduced menopausal symptoms, especially hot flashes,¹⁶ and Woods et al found that daily intake of a soy bar containing 40 mg of isoflavones effected a small decrease in menopausal symptoms over 12 weeks.¹⁷

Not all study findings have been as encouraging, however. Baird et al analyzed the effects of soy supplementation (165 mg/d of isoflavones) in postmenopausal women for 4 weeks.¹⁸ They found no significant estrogenic effect of soy on serum levels of luteinizing hormone, follicle-stimulating hormone, or SHBG, although the diet had a small estrogenic effect on vaginal tissue. Three recent studies showed mixed results in terms of the effects of soy isoflavones on vasomotor symptoms in menopausal women.^19-21 Thus, it may be necessary to temper initial enthusiasm regarding the benefits of soy on hot flashes.

Vaginal Epithelium
Duncan et al assessed the effects of soy powders containing three different levels of isoflavones on the vaginal epithelium in 18 postmenopausal women.²² They found no significant effects of soy or isoflavone consumption on vaginal cytologic findings, and they reported that isoflavones had modest effects on plasma hormone levels. In contrast, Wilcox et al found a significant estrogenic effect on the vaginal epithelium in women who received dietary supplementation with soy flour, red clover sprouts, or flaxseed for 6 weeks.²³

Bone Mineral Density
Some animal studies have shown that soy has a proestrogenic effect on bone. Arjmandi et al measured bone mineral density (BMD) in ovariectomized rats given dietary soy protein or estrogen supplementation.²⁴ Soy intake inhibited bone loss, although not to the same extent as that achieved with estrogen. Blair et al also conducted a study on ovariectomized rats, and found that genistein preserved bone and suppressed osteoclast activity, both in vitro and in vivo.²⁵

Several studies conducted on humans have supported the role of soy in preserving bone health. Erdman et al discovered that BMD of the lumbar spine increased in menopausal women who received 55 to 90 mg of isoflavones daily for 6 months.²⁶ In the same study, placebo recipients had the lowest BMDs and the fastest bone loss, and estrogen recipients had the highest BMDs and the slowest bone loss. A more recent study determined that a soy protein isolate containing 80 mg of isoflavones daily for 24 weeks attenuated bone loss in the lumbar spine in perimenopausal women.²⁷

Clinicians should also know that many soy foods are rich in calcium, and offer as much or more calcium than does a serving of a dairy product.

Heart Disease
Potential mechanisms by which soy protein and/or isoflavones reduce blood cholesterol include effects on thyroid status (increasing thyroxine levels) and on bile acid balance, as well as the estrogenic effects of genistein and daidzein. Some studies have suggested that genistein is a powerful antioxidant,^28-31 and that soy intake inhibits oxidation of LDL cholesterol.³² Other mechanisms by which soy phytoestrogens affect the formation of atherosclerotic plaques include inhibition of angiogenesis, growth factors, and cell adhesion,³³ and inhibition of platelet aggregation.³⁴ It is also possible that persons who consume large amounts of soy protein in their diets are forgoing consumption of foods that are relatively high in saturated fat and cholesterol; thus, they are gaining an indirect blood cholesterol-lowering effect from soy.

By far, the most compelling evidence of soy's benefits in this regard comes from a meta-analysis of 38 clinical trials, which showed that consumption of soy protein, relative to that of animal protein, significantly lowered serum concentrations of total cholesterol, LDL cholesterol, and triglycerides.³⁵ Many other studies have shown similar benefits,^36-38 although a recent investigation showed less dramatic effects of soy on lipid levels.³⁹ Although the mechanisms underlying the beneficial effect of soy protein on lipid profiles are not fully understood, the US Food and Drug Administration announced in October 1999 that consumption of 25 g of soy protein daily can lower the risk of coronary heart disease.

Breast Cancer
Many menopausal women are concerned about the increased risk of breast cancer associated with use of estrogen replacement therapy (ERT) or hormone replacement therapy (HRT), particularly over the long term. Most of the research on soy (in terms of lowering breast cancer risk) has been conducted on women who consume large amounts of soy in their diets from a young age onward (eg, Japanese or Chinese women).

Much evidence in the literature supports the breast cancer-preventing effects of soy. Several studies have demonstrated that Asian women who consume a traditional, low-fat, high-soy diet have a four- to six-fold lower risk of developing breast cancer.⁴⁰ In fact, soy-derived isoflavones such as genistein and daidzein appear to protect against a variety of cancers. Biochemical mechanisms underlying the anticancer action of genistein include antiestrogenic effects, induction of cell differentiation, inhibition of cancer-inducing enzymes, antioxidant effects, and antiangiogenesis effects. Dietary phytoestrogens also inhibit cancer cell growth by competing with estradiol for type II estrogen binding sites.⁴¹

Animal studies provide even more convincing evidence for soy's protective effect against breast cancer.⁴² Among 26 animal studies of experimental carcinogenesis in which diets containing soy or soybean isoflavones were used, 17 reported protective effects, and none reported that soy intake increased tumor development. Epidemiologic data showed that consumption of nonfermented soy products, such as soymilk and tofu, tended to be protective or unassociated with cancer risk, whereas no consistent pattern was evident with fermented soy products such as miso. Protective effects of soy were observed for both hormone- and non-hormone-related cancers.

Although scientists have studied the effects of soy consumption on breast cancer risk in women who have eaten it throughout their lives, as well as the antitumor effects of soy in animals and in the laboratory, they do not have much information on women who begin to ingest large quantities of soy later in life or in those who have had breast cancer. Two reports have suggested that soy intake may not be totally safe in women with breast cancer or in those at high risk for the disease.^43,44 A laboratory study showed that low-dose genistein stimulated growth of estrogen-sensitive breast cancer cells, although higher doses of genistein inhibited such growth.⁴³ In the second investigation, researchers examined nipple fluid aspirated from 50 premenopausal women who were at high risk for breast cancer.⁴⁴ After a 3-month, soy-free period, during which samples of nipple fluid, blood, and urine were taken, subjects added two daily servings of a soy-based, nutritional beverage powder containing 70 mg of genistein to their diet for 12 months. Thus far, researchers have found that soy increased the amount of nipple aspirate fluid, which may or may not have implications in terms of breast cancer risk.

Questions regarding the breast cancer-protective effects of soy, as well as the safety of soy intake in postmenopausal women and in women with breast cancer, still remain. Clearly, more research in this area is needed. Regardless, the benefits of soy on hot flashes, vaginal dryness, lipid profiles, and BMD should be weighed against potential risks.

Endometrial Cancer
Thus far, research data suggest that soy does not exert estrogenic effects on the endometrium. Instead, it likely serves as an estrogen antagonist, and is associated with low rates of endometrial cancer in countries where soy intake is high. Goodman et al conducted a case-control, multiethnic population study to examine the role of dietary soy, fiber, and related foods and nutrients on the risk for endometrial cancer.⁴⁵ They found that a higher consumption of soy products and other legumes was associated with a decreased risk for endometrial cancer. Consumption of other sources of phytoestrogens (eg, whole grains, vegetables, fruits, seaweed) provided similar benefits.

RECOMMENDATIONS
Women who wish to increase soy phytoestrogen intake should start with food sources. Those who wish to augment dietary intake or to achieve higher levels of soy isoflavones to manage particular clinical conditions might consider adding soy protein, soy isoflavone powders, or soy isoflavone-encapsulated products. In choosing among these various products, they should read labels carefully for soy isoflavone content, particularly that of genistein and daidzein. If they are more interested in the benefits of the protein in soy, then they should determine the total protein content of the supplement. Also, they should be aware that the simple sugar content in some soy products is very high. Finally, they should consider choosing non- genetically-modified, organically grown soy products. TFP

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